The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.
Humans ; Parkinson Disease/pathology* ; alpha-Synuclein/metabolism* ; Dopaminergic Neurons/metabolism* ; Pars Compacta/metabolism*

Parkinson's disease (PD) is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta. The mutation of leucine-rich repeat kinase 2 (Lrrk2) is the most common autosomal dominant mutation in PD, and it has also been reported in sporadic cases. A growing body of research suggests that circadian rhythm disruption, particularly sleep-wake abnormality, is common during the early phase of PD. Our present study aimed to evaluate the impact of sleep deprivation (SD) on motor ability, sleep performance, and PD pathologies in Lrrk2^G2019S transgenic mice. After two months of SD, Lrrk2^G2019S mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits, a reduced striatal DA level, degenerated DAergic neurons, and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain. All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up. Moreover, a significant increase in α-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age. Taken together, our findings indicate that sleep abnormalities, as a risk factor, may contribute to the pathogenesis and progression of PD. Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.
Animals ; Electroencephalography ; Leucine/genetics* ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics* ; Mice ; Mice, Transgenic ; Mutation ; Parkinson Disease/metabolism* ; Sleep Deprivation/complications* ; alpha-Synuclein/genetics*

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). Genetic vulnerability, aging, environmental insults are believed to contribute to the pathogenesis of PD. However, the cellular and molecular mechanism of dopaminergic neurons degeneration remains incompletely understood. Dopamine (DA) metabolism is a cardinal physiological process in dopaminergic neurons, which is closely related to the loss of dopaminergic neurons in the SN. DA metabolism takes part in several pathological processes of PD neurodegeneration, such as iron metabolism disturbance, α-synuclein mis-folding, endoplasmic reticulum stress, protein degradation dysfunction, neuroinflammatory response, etc. In this review, we will describe altered DA metabolism and its contributions to PD pathogenesis.
Dopamine ; Dopaminergic Neurons ; Humans ; Parkinson Disease/etiology* ; Substantia Nigra ; alpha-Synuclein/metabolism*

OBJECTIVE: To investigate the effect of curcumin on dopamine neurons in Parkinson's disease (PD) and its mechanism. METHODS: SH-SY5Y human neuroblastoma cells were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish the PD cell model. The model cells were treated with curcumin and/or autophagy inhibitor 3-MA. After 48 h of drug treatment, the number of surviving dopamine neurons was detected by tyrosine hydroxylase immunofluorescence method. Western blotting was used to detect protein expression of α-Synuclein (α-Syn), transcription factor EB (TFEB) and autophagy-related proteins lysosome-associated membrane protein 2A (LAMP2A) and microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ); RT-PCR was used to detect mRNA expression of α-Syn. RESULTS: Compared with MPTP model group, curcumin increased the number of surviving dopamine neurons(<0.01), decreased both protein expression and mRNA expression of α-Syn (all <0.01), and increased protein expression of TFEB, LAMP2A and LC3-Ⅱ (all <0.01). When curcumin and 3-MA were given concurrently, the number of surviving dopamine neurons, protein expression of TFEB, LAMP2A and LC3-Ⅱ increased (<0.05 or <0.01), and both protein expression and mRNA expression of α-Syn decreased (<0.05 or <0.01) compared with MPTP model group; but the number of surviving dopamine neurons and protein expression of LAMP2A and LC3-Ⅱ decreased compared with curcumin group (all <0.05). CONCLUSIONS Curcumin exerts protective effect on dopamine neurons in PD, which may be associated with enhancing autophagy and promoting the clearance of α-Syn.
Animals ; Cell Line ; Curcumin ; pharmacology ; Dopaminergic Neurons ; drug effects ; Humans ; Mice ; Mice, Inbred C57BL ; Parkinson Disease ; alpha-Synuclein ; metabolism

Animals ; Dopamine ; metabolism ; Dopaminergic Neurons ; metabolism ; Humans ; Iron ; metabolism ; Oxidative Stress ; Parkinson Disease ; metabolism ; Pars Compacta ; metabolism ; alpha-Synuclein ; metabolism

Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD. In this review, we summarized the role of PD-associated proteins in autophagy pathways. In addition, we described the efficacy of autophagy-modulating compounds in PD models and discussed promising strategies for PD therapy.
Animals ; Autophagy ; Humans ; Parkinson Disease ; physiopathology ; Protein Kinases ; metabolism ; Ubiquitin-Protein Ligases ; metabolism ; alpha-Synuclein ; metabolism

OBJECTIVES: To observe the changes of expression of α-synuclein （α-syn） and neuronal apoptosis in brain cortex of acute alcoholism rats and to explore the mechanism of the damage caused by ethanol to the neurons. METHODS: The model of acute alcoholism rat was established by 50% alcohol gavage. The α-syn and caspase-3 were detected by immunohistochemical staining and imaging analysis at 1 h, 3 h, 6 h and 12 h after acute alcoholism. The number of positive cell and mean of optical density were detected and the trend change was analyzed. The variance analysis and t-test were also performed. RESULTS: The number of α-syn positive cell and average optical density in brain cortex of acute alcoholism rat increased significantly and peaked at 6 hour with a following slight decrease at 12 h, but still higher than the groups at 1 h and 3 h. Within 12 hours after poisoning, the number of caspase-3 positive cell and average optical density in brain cortex of rats gradually increased. CONCLUSIONS The abnormal aggregation of α-syn caused by brain edema and hypoxia may participate the early stage of neuronal apoptosis in brain cortex after acute alcoholism.
Alcoholism/pathology* ; Animals ; Apoptosis ; Brain Edema/pathology* ; Caspase 3/metabolism* ; Cerebral Cortex/pathology* ; Ethanol ; Hypoxia/pathology* ; Neurons/pathology* ; Rats ; alpha-Synuclein/metabolism*

OBJECTIVETo investigate the effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels (mitoKATP) induced by overexpression or mutation of &alpha;-synuclein.

METHODSRecombinant plasmids &alpha;-synuclein-pEGFP-A53T and &alpha;-synuclein-pEGFP-WT were transfected into PC12 cells by lipofectamin method, and intervened by application of curcumin (20 μmol/L) and 5-hydroxydecanoate (5-HD). Oligomer formation in the cultured cells was identified by Western blotting and Dot blotting. Cytotoxicity and apoptosis of the PC12 cells were measured by lactate dehydrogenase (LDH) and JC-1 assays. mitoKATP were identified by Western blotting and whole cell patch clamp.

RESULTSCurcumin has significantly reduced the oligomer formation induced by overexpression or mutation of &alpha;-synuclein in the cultured cells. LDH has decreased by 36.3% and 23.5%, and red/green fluorescence ratio of JC-1 was increased respectively by 48.46% and 50.33% after application of curcumin (P<0.05). Protein expression of Kir6.2 has decreased and mitoKATP channel current has significantly increased (P<0.05).

CONCLUSIONCurcumin can inhibit &alpha;-synuclein gene overexpression or mutation induced &alpha;-synuclein oligomers formation. It may block apoptosis induced by wild-type overexpression or mutation of &alpha;-synuclein. By stabilizing mitochondrial membrane potential. Opening of mitoKATP channel may have been the initiating protective mechanism of apoptosis induced by wild-type overexpression or mutation of &alpha;-synuclein. Curcumin may antagonize above cytotoxicity through further opening the mitoKATP channel.

Animals ; Apoptosis ; drug effects ; Cell Line ; Curcumin ; pharmacology ; Humans ; KATP Channels ; chemistry ; genetics ; metabolism ; Mitochondria ; drug effects ; genetics ; metabolism ; Mutation ; drug effects ; PC12 Cells ; Parkinson Disease ; drug therapy ; genetics ; metabolism ; physiopathology ; Rats ; alpha-Synuclein ; genetics

OBJECTIVETo investigate histopathology and proteinopathy in the spinal cord of patients with common neurodegenerative diseases.

METHODSSpinal cord tissues from clinically and neuropathologically confirmed neruodegnerative diseases were enrolled in this study, including 3 cases of multiple system strophy, 4 cases of amyotrophic lateral sclerosis, 5 cases of Alzheimer's disease (AD, included 2 cases of AD combined with Parkinson's disease), 2 cases of progressive supranuclear palsy, 1 case of dementia with lewy body and 1 case of corticobasal degeneration from 1955 to 2013 at Chinese People's Liberation Army General Hospital. Four normal control cases were also included. Routine HE and Gallyas-Braak staining, and immunohistochemical stainings for anti-PHF tau (AT8), anti-&alpha;-synuclein, anti-TDP-43 and anti-ubiquitin were performed.

RESULTSExamination of the spinal cord in 3 cases with multiple system strophy revealed severe neuron loss in the intermediolateral nucleus of thoracic segment and Onuf's nucleus of the sacral segment, along with moderate neuron loss in the anterior horn of the cervical segment and mild myelin pallor in the anterior funiculus and anterolateral funiculus in the cervical and thoracic segments. Large amount of argentophilic, ubiquitin and synuclein positive oligodendroglial cytoplasmic inclusions were found widely distributed in the anterior horn and the anterior funiculus and anterolateral funiculus of the full spinal cord. Severe neuron loss and several morphological changes with gliosis in the anterior horn and severe loss of myelin in the anterior funiculus and anterolateral funiculus of the full spinal cord were observed in 4 cases of amyotrophic lateral sclerosis, 2 of which were found with Bunina bodies in neurons of the anterior horn. Three amyotrophic lateral sclerosis cases had ubiquitin-positive neuronal inclusions and TDP-43 positive neuronal and glial inclusions in the anterior horn at cervical and lumbar segments. A few argentophilic, tau positive neurofibrillary tangles (NFTs) and neuropil threads in the anterior horn at cervical and lumbar segments were found in 4 AD cases. Examination of spinal cord in 2 cases with Parkinson's disease combined with AD and 1 case with dementia with lewy body revealed severe neuron loss in the intermediolateral nucleus of thoracic segment, and a few synuclein positive lewy bodies and neuritis were also observed. There was mild neuron loss in the anterior horn at cervical and lumbar segments, along with some argentophilic, tau positive globous NFTs and many argentophilic, tau positive neutrophil threads were observed in 2 progressive supranuclear palsy cases and 1 corticobasal degeneration case.

CONCLUSIONEach common neurodegenerative diseases of the spinal cord including multiple system strophy, amyotrophic lateral sclerosis and Parkinson's disease has its own specific histopathology and proteinopathy characteristics.

Alzheimer Disease ; pathology ; Amyotrophic Lateral Sclerosis ; pathology ; DNA-Binding Proteins ; metabolism ; Humans ; Immunohistochemistry ; Inclusion Bodies ; pathology ; Neurodegenerative Diseases ; pathology ; Neurofibrillary Tangles ; pathology ; Neurons ; pathology ; Parkinson Disease ; pathology ; Spinal Cord ; pathology ; Ubiquitin ; metabolism ; alpha-Synuclein ; metabolism

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into beta-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Animals ; Autophagy/drug effects ; DNA-Binding Proteins/metabolism ; Humans ; Huntington Disease/drug therapy/genetics/metabolism ; Lysosomes/metabolism ; Molecular Targeted Therapy ; Mutation ; Nerve Tissue Proteins/genetics/metabolism ; Neurodegenerative Diseases/drug therapy/*metabolism ; Parkinson Disease/drug therapy/metabolism ; PrPSc Proteins/metabolism ; Prion Diseases/drug therapy/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Proteostasis Deficiencies/metabolism ; Superoxide Dismutase/metabolism ; Ubiquitin/metabolism ; alpha-Synuclein/metabolism ; tau Proteins/metabolism